Tag: tryptophan

Plasma taurine level is linked to symptom burden and clinical outcomes in post-COVID condition

Abstract:

Background: A subset of individuals (10-20%) experience post-COVID condition (PCC) subsequent to initial SARS-CoV-2 infection, which lacks effective treatment. PCC carries a substantial global burden associated with negative economic and health impacts. This study aims to evaluate the association between plasma taurine levels with self-reported symptoms and adverse clinical outcomes in patients with PCC.

Methods and findings: We analyzed the plasma proteome and metabolome of 117 individuals during their acute COVID-19 hospitalization and at the convalescence phase six-month post infection. Findings were compared with 28 age and sex-matched healthy controls. Plasma taurine levels were negatively associated with PCC symptoms and correlated with markers of inflammation, tryptophan metabolism, and gut dysbiosis. Stratifying patients based on the trajectories of plasma taurine levels during six-month follow-up revealed a significant association with adverse clinical events. Increase in taurine levels during the transition to convalescence were associated with a reduction in adverse events independent of comorbidities and acute COVID-19 severity. In a multivariate analysis, increased plasma taurine level between acute and convalescence phase was associated with marked protection from adverse clinical events with a hazard ratio of 0.13 (95% CI: 0.05-0.35; p<0.001).

Conclusions: Taurine emerges as a promising predictive biomarker and potential therapeutic target in PCC. Taurine supplementation has already demonstrated clinical benefits in various diseases and warrants exploration in large-scale clinical trials for alleviating PCC.

Source: Khoramjoo M, Wang K, Srinivasan K, Gheblawi M, Mandal R, Rousseau S, Wishart D, Prasad V, Richer L, Cheung AM, Oudit GY. Plasma taurine level is linked to symptom burden and clinical outcomes in post-COVID condition. PLoS One. 2024 Jun 5;19(6):e0304522. doi: 10.1371/journal.pone.0304522. PMID: 38837993; PMCID: PMC11152273. https://pmc.ncbi.nlm.nih.gov/articles/PMC11152273/ (Full text)

Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide.

To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry.

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Source: Abujrais S, Vallianatou T, Bergquist J. Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry. ACS Chem Neurosci. 2024 Sep 20. doi: 10.1021/acschemneuro.4c00444. Epub ahead of print. PMID: 39302151. https://pubs.acs.org/doi/10.1021/acschemneuro.4c00444 (Full text)

Fast Targeted Metabolomics for Analyzing Metabolic Diversity of Bacterial Indole Derivatives in ME/CFS Gut Microbiome

Abstract:

Disruptions in microbial metabolite interactions due to gut microbiome dysbiosis and metabolomic shifts may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and other immune-related conditions. The aryl hydrocarbon receptor (AhR), activated upon binding various tryptophan metabolites, modulates host immune responses. This study investigates whether the metabolic diversity-the concentration distribution-of bacterial indole pathway metabolites can differentiate bacterial strains and classify ME/CFS samples.

A fast targeted liquid chromatography-parallel reaction monitoring method at a rate of 4 minutes per sample was developed for large-scale analysis. This method revealed significant metabolic differences in indole derivatives among B. uniformis strains cultured from human isolates. Principal component analysis identified two major components (PC1, 68.9%; PC2, 18.7%), accounting for 87.6% of the variance and distinguishing two distinct B. uniformis clusters. The metabolic difference between clusters was particularly evident in the relative contributions of indole-3-acrylate and indole-3-aldehyde.

We further measured concentration distributions of indole derivatives in ME/CFS by analyzing fecal samples from 10 patients and 10 healthy controls using the fast targeted metabolomics method. An AdaBoost-LOOCV model achieved moderate classification success with a mean LOOCV accuracy of 0.65 (Control: precision of 0.67, recall of 0.60, F1-score of 0.63; ME/CFS: precision of 0.64, recall of 0.7000, F1-score of 0.67).

These results suggest that the metabolic diversity of indole derivatives from tryptophan degradation, facilitated by the fast targeted metabolomics and machine learning, is a potential biomarker for differentiating bacterial strains and classifying ME/CFS samples.

Mass spectrometry datasets are accessible at the National Metabolomics Data Repository (ST002308, DOI: 10.21228/M8G13Q; ST003344, DOI: 10.21228/M8RJ9N; ST003346, DOI: 10.21228/M8RJ9N).

Source: Tian H, Wang L, Aiken E, Ortega RJV, Hardy R, Placek L, Kozhaya L, Unutmaz D, Oh J, Yao X. Fast Targeted Metabolomics for Analyzing Metabolic Diversity of Bacterial Indole Derivatives in ME/CFS Gut Microbiome. bioRxiv [Preprint]. 2024 Jul 29:2024.07.29.605643. doi: 10.1101/2024.07.29.605643. PMID: 39131327; PMCID: PMC11312560. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11312560/ (Full text)

BioMapAI: Artificial Intelligence Multi-Omics Modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Abstract:

Chronic diseases like ME/CFS and long COVID exhibit high heterogeneity with multifactorial etiology and progression, complicating diagnosis and treatment. To address this, we developed BioMapAI, an explainable Deep Learning framework using the richest longitudinal multi-‘omics dataset for ME/CFS to date.

This dataset includes gut metagenomics, plasma metabolome, immune profiling, blood labs, and clinical symptoms. By connecting multi-‘omics to asymptom matrix, BioMapAI identified both disease- and symptom-specific biomarkers, reconstructed symptoms, and achieved state-of-the-art precision in disease classification. We also created the first connectivity map of these ‘omics in both healthy and disease states and revealed how microbiome-immune-metabolome crosstalk shifted from healthy to ME/CFS.

Thus, we proposed several innovative mechanistic hypotheses for ME/CFS: Disrupted microbial functions – SCFA (butyrate), BCAA (amino acid), tryptophan, benzoate – lost connection with plasma lipids and bile acids, and activated inflammatory and mucosal immune cells (MAIT, γδT cells) with INFγ and GzA secretion. These abnormal dynamics are linked to key disease symptoms, including gastrointestinal issues, fatigue, and sleep problems.

Source: Xiong R, Fleming E, Caldwell R, Vernon SD, Kozhaya L, Gunter C, Bateman L, Unutmaz D, Oh J. BioMapAI: Artificial Intelligence Multi-Omics Modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. bioRxiv [Preprint]. 2024 Jun 28:2024.06.24.600378. doi: 10.1101/2024.06.24.600378. PMID: 38979186; PMCID: PMC11230215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11230215/ (Full text available as PDF file)

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

Abstract:

The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2 invades enterochromaffin cells rich in ACE2 receptors and curtails absorption of the essential amino acid tryptophan and subsequent synthesis of serotonin and melatonin.

This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease.

Source: Chambers, P.W.; Chambers, S.E. Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach. Preprints 2023, 2023121881. https://doi.org/10.20944/preprints202312.1881.v2 https://www.preprints.org/manuscript/202312.1881/v2 (Full text available as PDF file)

Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study

Abstract:

Background: Around 10% of people who had COVID-9 infection suffer from persistent symptoms such as fatigue, dyspnoea, chest pain, arthralgia/myalgia, sleep disturbances, cognitive dysfunction and impairment of mental health. Different underlying pathomechanisms appear to be involved, in particular inflammation, alterations in amino acid metabolism, autonomic dysfunction and gut dysbiosis.

Aim: As routine tests are often inconspicuous in patients with Long COVID (LC), similarly to patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), accessible biomarkers indicating dysregulation of specific pathways are urgently needed to identify underlying pathomechanisms and enable personalized medicine treatment. Within this pilot study we aimed to proof traceability of altered metabolism by urine analysis.

Patients and methods: Urine metabolome analyses were performed to investigate the metabolic signature of patients with LC (n = 25; 20 women, 5 men) in comparison to healthy controls (Ctrl, n = 8; 7 women, 1 man) and individuals with ME/CFS (n = 8; 2 women, 6 men). Concentrations of neurotransmitter precursors tryptophan, phenylalanine and their downstream metabolites, as well as their association with symptoms (fatigue, anxiety and depression) in the patients were examined.

Results and conclusion: Phenylalanine levels were significantly lower in both the LC and ME/CFS patient groups when compared to the Ctrl group. In many LC patients, the concentrations of downstream metabolites of tryptophan and tyrosine, such as serotonin, dopamine and catecholamines, deviated from the reference ranges. Several symptoms (sleep disturbance, pain or autonomic dysfunction) were associated with certain metabolites. Patients experiencing fatigue had lower levels of kynurenine, phenylalanine and a reduced kynurenine to tryptophan ratio (Kyn/Trp). Lower concentrations of gamma-aminobutyric acid (GABA) and higher activity of kynurenine 3-monooxygenase (KMO) were observed in patients with anxiety.

Conclusively, our results suggest that amino acid metabolism and neurotransmitter synthesis is disturbed in patients with LC and ME/CFS. The identified metabolites and their associated dysregulations could serve as potential biomarkers for elucidating underlying pathomechanisms thus enabling personalized treatment strategies for these patient populations.

Source: Taenzer M, Löffler-Ragg J, Schroll A, Monfort-Lanzas P, Engl S, Weiss G, Brigo N, Kurz K. Urine Metabolite Analysis to Identify Pathomechanisms of Long COVID: A Pilot Study. Int J Tryptophan Res. 2023 Dec 22;16:11786469231220781. doi: 10.1177/11786469231220781. PMID: 38144169; PMCID: PMC10748708. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10748708/ (Full text)

Serotonin reduction in post-acute sequelae of viral infection

Highlights:

  • Long COVID is associated with reduced circulating serotonin levels
  • Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs)
  • IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability
  • Peripheral serotonin deficiency impairs cognition via reduced vagal signaling

Summary:

Post-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction.
Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
Source: Wong et al., Serotonin reduction in post-acute sequelae of viral infection, Cell (2023), https://doi.org/
10.1016/j.cell.2023.09.013 https://www.cell.com/cell/fulltext/S0092-8674(23)01034-6 (Full text)

Treatment of Brain Fog of Long COVID Syndrome: A Hypothesis

Abstract:

The emergence of the SARS-CoV-2 (COVID-19) virus has exacted a significant toll on the global population in terms of fatalities, health consequences, and economics. As of February 2023, there have been almost 800 million confirmed cases of the disorder reported to the WHO [1], although the actual case-positive rate is estimated to be much higher.

While many cases recover, the mortality rate associated with the illness is about 1% (based on the WHO data). Most patients experience the illness as a mild to moderate disorder and recover without significant sequelae. However, as the COVID-19 pandemic has continued, there has emerged a significant group of COVID-19 survivors who experience persistent symptoms beyond the acute course of the illness.

As many as one in eight patients report persistent symptoms 90 to 150 days after the initial infection [2]. These so-called Long COVID or post-COVID syndrome patients are mostly drawn from those who were hospitalised for the disorder, but both non-hospitalised and vaccinated subjects may also experience the syndrome [3]. While an agreed definition of Long COVID is yet to be settled, a multiplicity of symptoms affecting most major organ systems has been reported in patients.

Common Long COVID symptoms include fatigue, dyspnoea, headaches, myalgia, anosmia, dysgeusia, cognitive symptoms, and mental disorders such as depression and anxiety [4]. It is estimated that approximately a third of patients with Long COVID exhibit either fatigue, cognitive impairment, or both up to 12 weeks after a confirmed diagnosis of COVID-19 [5].

Source: Norman TR. Treatment of Brain Fog of Long COVID Syndrome: A Hypothesis. Psychiatry International. 2023; 4(3):242-245. https://doi.org/10.3390/psychiatryint4030024 https://www.mdpi.com/2673-5318/4/3/24 (Full text)

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID

Abstract:

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.

In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3–10 months after remission of acute infection.

We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome.

Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19).

In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.

Source: Al-Hakeim HK, Khairi Abed A, Rouf Moustafa S, Almulla AF, Maes M. Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID. Front Mol Neurosci. 2023 Jun 2;16:1194769. doi: 10.3389/fnmol.2023.1194769. PMID: 37333619; PMCID: PMC10272345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272345/ (Full text)

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on individuals and their community. Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers.

To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated; however, these studies have failed to report a consistent result. These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP).

KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH). In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites. This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS.

Source: Kavyani B, Lidbury BA, Schloeffel R, Fisher PR, Missailidis D, Annesley SJ, Dehhaghi M, Heng B, Guillemin GJ. Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle? Cell Mol Life Sci. 2022 Jul 11;79(8):412. doi: 10.1007/s00018-022-04380-5. PMID: 35821534. https://link.springer.com/article/10.1007/s00018-022-04380-5  (Full text)